The overall goal of this Program Project is to define how in vivo measurements of tumor metabolism can be used to predict and evaluate response to therapy. These measurements will be made with positron emission tomography (PET) imaging of the uptake of several different radiopharmaceuticals. Project 1 will measure metabolism of [C-11] glucose and [F-18] fluorodeoxyglucose in gliomas. Project 3 will measure DNA synthetic rate with [C-11] thymidine in patients with lymphoma, lung cancer, and soft tissue sarcomas. Project 9 will define the accuracy of PET derived estimates of metabolic parameters by looking at the effect of noise and tissue heterogeneity on those estimates. Project 10 will measure estrogen receptor density in primary and metastatic breast cancer with [F-18] fluoroestradiol. Project 6 will measure the uptake of [F-18] fluoromisonidazole, an agent that localizes in hypoxic tissue, to measure tumor hypoxia in non-small cell lung, head and neck, and prostate tumors. In each project we emphasize quantitative measurements of uptake kinetics using physiologically reasonable models for the data analysis. The projects are supported by 3 technical cores: 9001 (Radiochemistry) will supply the radiopharmaceuticals needed by the projects; 9002 (Physics) will support the tomograph and imaging computers as well as develop important software for image reconstruction, image registration, and partial volume correction; 9004 (Imaging and Data Analysis) will provide the expertise to perform the tomographic studies and the software tools to analyze the data as well as provide statistical support for the projects. These tools include an image manipulation program, several parameter optimization programs for the various radiotracers, and a set of programs to generate metabolic images. The previously funded work in this Program Project has progressed through cell culture, rodent tumors, and dog tumor studies to preliminary human studies to preliminary human studies. We have established the validity of the methodology and are now prepared to apply these techniques to larger numbers of human tumors. We will test the hypothesis that metabolic measures of tumor metabolism are more sensitive than conventional methods such as monitoring tumor size by CT or MRI. The goals of each project include simplifying the protocols by minimizing the numbers of images and the necessity for blood sampling to make the methodology more widely available. There is now considerable interest in the application of PET in cardiology and neurology as well as in oncology. PET is a powerful tool capable of non-invasive measurements of tissue metabolism, however, it is complex and expensive. Early studies must be done carefully and quantitatively in order to clearly define the capabilities of PET in these areas. This will result in the effective use of PET for research and clinical care in the future.